The chemokines had been characterized into about 50 types up to now as physiologically active proteins acting on immune system in human body and are classified into 4 groups including C, CC, CXC and CX3C based on the structural difference of conserved cystein sharing in amino acid sequence. Each chemokines bind to GPCR (G-protein-coupled receptor) and show their physiological action, where especially receptor with which MCP-1, CC chemokine, integrates is said to be CCR2. MCP-1 is known to play a major role in migration of monocytes during process leading to inflammation (reference: Nature Review Drug Discovery, 2002, 1, 347). For example, in rheumatoid arthritis overexpression of MCP-1 and CCR2 were identified (reference: Arthritis Rheum., 2001, 44, 2750) and the role of MCP-1 and CCR2 were also demonstrated by extensive research in knockout mouse (reference: Chemokine in Disease, 1999, 53-65).
Since CCR2 is considered to be a target of prominent drug of inflammatory diseases, several therapeutic agents for the inflammatory related several diseases could be developed based on the CCR2 antagonistic effect. For example, Johnson & Johnson tried to develop dipiperidine compounds as CCR2 antagonists. These compounds showed high affinity to CCR2 receptor and also blocked chemotaxis induced by MCP-1 in THP-1 cell lines (reference: WO2006-036527, WO2007-106797).
The Millenium also developed human monoclonal antibody MLN1202 as its therapeutic agent for inflammatory disease so that it demonstrated CCR2 to be a target of prominent drug of inflammatory disease, getting positive results from clinical trial aiming at arteriosclerosis.
Meanwhile obesity and insulin resistance, which is important characteristic of metabolic syndrome, is closely correlated with inflammation. If chronic overnutrition is lasting, macrophage in adipose tissue is infiltrated and thus the local inflammation is brought out, which intensifies the resistance to insulin. At this time inhibiting MCP-1 or its own receptor CCR2 suppresses migration of macrophage into adipose tissue, which may decrease inflammation in the adipose tissue and increase sensitivity to insulin. Based on the animal test result, it may be observed that the intake of CCR2 deficient mouse was decreased than normal one, but obesity was not developed obviously even with high fat diet (reference: Nature, 2007, 447, 1116).
The CCR2 could also be useful as therapeutic agent for Alzheimer's disease. The accumulative process of amyloid-beta, which is protein as form of plaque and is produced in the brain of Alzheimer's disease patients, is known to be associated with pathways of inflammatory response regulated by microglias, immune cells of brain and central nervous system. The CCR2 has a major role in migration of this microglia (reference: Nature Medicine, 2007, 13, 432).
It is prior art to have 3-aminopyrrolidine as core structure among low molecular weight compound representing antagonistic effect of CCR2 receptor. And it was proposed according to WO 2004-050024, for example, a representative structure where cycloalkane was integrated into 3-aminopyrrolidine. According to WO 2000-069432, the compound where alkyl and again aryl or cycloalkyl group were integrated into 3-aminopyrrolidine was suggested. The representative structure of such compounds were 3-amino-N-benzylpyrrolidine of which antagonistic action to CCR2 receptor had been already reported.
As suggested by WO 2003-075853, the compound was notified where arylsulfone group was substituted on the carbon atom of 3-aminopyrrolidine as more diverse structure compound including 3-aminopyrrolidine structure. Meanwhile, according to WO 2007-053495, WO 2007-053498, WO 2007-053499, cycloalkanes including heteroatoms which are connected to 3-aminopyrrolidine were also proposed.